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Aoyagi, A., Condello, C., Stöhr, J., Yue, W., Rivera, B. M., Lee, J. C., . . . Prusiner, S. B. (2019). A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain. Science Translational Medicine, 11(490), Article ID eaat8462.
Open this publication in new window or tab >>A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain
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2019 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 11, no 490, article id eaat8462Article in journal (Refereed) Published
Abstract [en]

The hallmarks of Alzheimer's disease (AD) are the accumulation of A beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of A beta in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological A beta conformers. Individuals over 80 years of age had the lowest amounts of prion-like A beta and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-383844 (URN)10.1126/scitranslmed.aat8462 (DOI)000466449900004 ()31043574 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationStockholm County Council
Available from: 2019-05-24 Created: 2019-05-24 Last updated: 2019-05-24Bibliographically approved
Vaikath, N. N., Hmila, I., Gupta, V., Erskine, D., Ingelsson, M. & El-Agnaf, O. M. A. (2019). Antibodies against alpha-synuclein: tools and therapies. Journal of Neurochemistry, 150(5), 612-625
Open this publication in new window or tab >>Antibodies against alpha-synuclein: tools and therapies
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2019 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 150, no 5, p. 612-625Article, review/survey (Refereed) Published
Abstract [en]

Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of alpha-synuclein (alpha-syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against alpha-syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated alpha-syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full-length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody-based approaches have been found to be promising as therapeutic strategies, both to block alpha-syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different alpha-syn specific antibodies and provide their usefulness in tackling synucleinopathies. 

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
antibodies, synucleinopathies, alpha-synuclein
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-394144 (URN)10.1111/jnc.14713 (DOI)000482407100012 ()31055836 (PubMedID)
Available from: 2019-10-04 Created: 2019-10-04 Last updated: 2019-10-04Bibliographically approved
Reyes, J. F., Sackmann, C., Hoffmann, A., Svenningsson, P., Winkler, J., Ingelsson, M. & Hallbeck, M. (2019). Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes. Acta Neuropathologica, 138(1), 23-47
Open this publication in new window or tab >>Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
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2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed) Published
Abstract [en]

The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Parkinson's disease (PD), Multiple system atrophy (MSA), Alzheimer's disease (AD), Cell-to-cell transfer, Prion-like transfer, Gap junction proteins, Cx32, GJB1, alpha-Synuclein (-syn)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-390089 (URN)10.1007/s00401-019-02007-x (DOI)000471708700002 ()30976973 (PubMedID)
Funder
Swedish Research Council, 523-2013-2735German Research Foundation (DFG), GRK2162
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved
Kunkle, B. W., Giedraitis, V., Kilander, L., Brundin, R., Lannfelt, L., Ingelsson, M. & Pericak-Vance, M. A. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414-430
Open this publication in new window or tab >>Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 414-430Article in journal (Refereed) Published
Abstract [en]

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379343 (URN)10.1038/s41588-019-0358-2 (DOI)000459947200011 ()30820047 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-019-0358-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Quaranta, A., Karlsson, I., Ndreu, L., Marini, F., Ingelsson, M. & Thorsen, G. (2019). Glycosylation profiling of selected proteins in cerebrospinal fluid from Alzheimer's disease and healthy subjects. Analytical Methods, 11(26), 3331-3340
Open this publication in new window or tab >>Glycosylation profiling of selected proteins in cerebrospinal fluid from Alzheimer's disease and healthy subjects
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2019 (English)In: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 11, no 26, p. 3331-3340Article in journal (Refereed) Published
Abstract [en]

Alteration of glycosylation has been observed in several diseases, such as cancer and neurodegenerative disorders. The study of changes in glycosylation could lead to a better understanding of mechanisms underlying these diseases and to the identification of new biomarkers. In this work the N-linked glycosylation of five target proteins in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients and healthy controls have been analyzed for the first time. The investigated proteins, transferrin (TFN), alpha-1-antitrypsin (AAT), C1-inhibitor, immunoglobulin G (IgG), and alpha-1-acid glycoprotein (AGP), were selected based on the availability of VHH antibody fragments and their potential involvement in neurodegenerative and inflammation diseases. AD patients showed alterations in the glycosylation of low abundance proteins, such as C1-inhibitor and alpha-1-acid glycoprotein. These alterations would not have been detected if the glycosylation profile of the total CSF had been analyzed, due to the masking effect of the dominant profiles of high abundance glycoproteins, such as IgG. Information obtained from single proteins was not sufficient to correctly classify the two sample groups; however, by using an advanced multivariate technique a total non-error rate of 72 +/- 3% was obtained. In fact, the corresponding model was able to correctly classify 71 +/- 4% of the healthy subjects and 74 +/- 7% of the AD patients. Even if the results were not conclusive for AD, this approach could be extremely useful for diseases in which glycosylation changes are reported to be more extensive, such as several types of cancer and autoimmune diseases.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-390784 (URN)10.1039/c9ay00381a (DOI)000474140100007 ()
Funder
Swedish Research Council, 2013-4353
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2019-08-16Bibliographically approved
Emami Khoonsari, P., Shevchenko, G., Herman, S., Remnestal, J., Giedraitis, V., Brundin, R., . . . Kultima, K. (2019). Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. Journal of Alzheimer's Disease, 67(2), 639-651
Open this publication in new window or tab >>Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed) Published
Abstract [en]

Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, cerebrospinal fluid, ELISA, mass spectrometry, mild cognitive impairment, proteomics
National Category
Neurology Geriatrics
Identifiers
urn:nbn:se:uu:diva-377711 (URN)10.3233/JAD-180855 (DOI)000457779300016 ()30614806 (PubMedID)
Funder
VINNOVAGun och Bertil Stohnes StiftelseÅke Wiberg FoundationStiftelsen Gamla Tjänarinnor
Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-04-29Bibliographically approved
Feresiadou, A., Nilsson, K., Ingelsson, M., Press, R., Kmezic, I., Nygren, I., . . . Burman, J. (2019). Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease. Journal of Neuroimmunology, 332, 31-36
Open this publication in new window or tab >>Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease
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2019 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-381319 (URN)10.1016/j.jneuroim.2019.03.015 (DOI)000470940600004 ()30928869 (PubMedID)
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-07-05Bibliographically approved
Forsberg, L. A., Halvardson, J., Rychlicka-Buniowska, E., Danielsson, M., Moghadam, B. T., Mattisson, J., . . . Dumanski, J. P. (2019). Mosaic loss of chromosome Y in leukocytes matters [Letter to the editor]. Nature Genetics, 51(1), 4-7
Open this publication in new window or tab >>Mosaic loss of chromosome Y in leukocytes matters
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 4-7Article in journal, Letter (Other academic) Published
National Category
Medical Genetics Genetics
Identifiers
urn:nbn:se:uu:diva-373366 (URN)10.1038/s41588-018-0267-9 (DOI)000454108800004 ()30374072 (PubMedID)
Funder
EU, European Research CouncilSwedish Research Council
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Carolina Dalmasso, M., Ignacio Brusco, L., Olivar, N., Muchnik, C., Hanses, C., Milz, E., . . . Ramirez, A. (2019). Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease. Translational Psychiatry, 9, Article ID 55.
Open this publication in new window or tab >>Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease
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2019 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, article id 55Article in journal (Refereed) Published
Abstract [en]

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-379282 (URN)10.1038/s41398-019-0394-9 (DOI)000459833200009 ()30705288 (PubMedID)
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-03-14Bibliographically approved
Gyorgy, B., Kleinstiver, B. P., Garcia, S. P., Zaborowski, M., Sousa, A. A., Tsai, S. Q., . . . Maguire, C. A. (2018). AAV-Vector Integration into CRISPR-Induced Double-Stranded Breaks. Paper presented at 21st Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 16-19, 2018, Chicago, USA.. Molecular Therapy, 26(5), 432-433
Open this publication in new window or tab >>AAV-Vector Integration into CRISPR-Induced Double-Stranded Breaks
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2018 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 26, no 5, p. 432-433Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-366837 (URN)10.1016/j.ymthe.2018.05.001 (DOI)000435342205163 ()
Conference
21st Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 16-19, 2018, Chicago, USA.
Note

Meeting Abstract: 951

Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5466-8370

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